Investigating how cytokine exposure rewires tumor cells, Dopler et al. found that activating cytokines like IFNγ, TNFα, IFNα/β, IL-1β, IL-6, and IL-17A, promoted the incorporation of P-stalk into ribosomes. Within cells, P-stalk ribosomes (PSRs) supported the preferential translation of mRNAs, particularly those encoding antigen processing and presentation machinery and other cytokine-regulated processes, enabling an “alert” state and increased susceptibility to immune detection and clearance. Loss of PSRs inhibited CD8+ T cell recognition and killing, and TGFβ was found to inhibit PSRs. P-stalk incorporation appeared to be transcriptionally regulated, while P-stalk inhibition was regulated by phosphorylation.
Contributed by Lauren Hitchings
ABSTRACT: Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an "alert state" that enhances their visibility to the immune system. Here, we identified an alert-state subpopulation of ribosomes defined by the presence of the P-stalk. We show that P-stalk ribosomes (PSRs) are formed in response to cytokines linked to tumor immunity, and this is at least partially mediated by P-stalk phosphorylation. PSRs are involved in the preferential translation of mRNAs vital for the cytokine response via the more efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the PSR inhibits CD8+ T cell recognition and killing, and inhibitory cytokines like transforming growth factor β (TGF-β) hinder PSR formation, suggesting that the PSR is a central regulatory hub upon which multiple signals converge. Thus, the PSR is an essential mediator of the cellular rewiring that occurs following cytokine exposure via the translational regulation of this process.
Author Info: (1) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (3)
Author Info: (1) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (3) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (10) Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (16) Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (17) Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (18) Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Cellular Biology Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (21) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: w.faller@nki.nl.
